Carmoterol, chemically termed as 8-hydroxy-5-[1-hydroxy{[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl]-2(1H)-quinolinone, is a highly potent β2-selective adrenoceptor agonist having a long lasting bronchodilating effect. The structure of carmoterol is as shown below:

The asterisks indicate that carmoterol has two chiral centers in the molecule, each of which can exist in two possible configurations (R or S). This gives rise to four possible configurations of carmoterol: (R, R), (S, S), (S, R) and (R, S). Throughout this specification, the first “R” or “S” refers to the configuration of the asymmetric carbon atom at the position of —CH(OH)— and the second “R” or “S” refers to the configuration of the asymmetric carbon atom at the position of —CH(CH3)—. For example, the term “R,S” refers to the diastereomer of carmoterol wherein the asymmetric carbon atom at the position of —CH(OH)— has the R configuration and the asymmetric carbon atom at the position of —CH(CH3)— has the S configuration. (R, R) and (S, S) are minor images of each other and are therefore enantiomers. These two enantiomers are referred to as α-isomers. Similarly, (S, R) and (R, S) are an enantiomeric pair and are referred to as β-isomers.
All four isomers of carmoterol have been synthesized and the (R, R) isomer is reported to be the most potent, while the others are less potent.
Carmoterol and its isomers were first disclosed in the U.S. Pat. No. 4,579,854. The process is disclosed in preparation 1 and in examples 2, 3 and 4. The synthetic process employed is depicted in the following Scheme 1.

A similar process is disclosed in example (5) of U.S. Pat. No. 4,579,854, where compound (e) is reacted with optically pure (R)—N-(2-(p-methoxyphenyl)-1-methylethylamine of compound (f) to give a diastereomeric mixture of carmoterol, which diastereomers are then separated by column chromatography to give the R,R and S,S isomers. These isomers are hydrolysed and reduced to give R, R-carmoterol.
The preparation of optically pure (R)-8-benzyloxy-5-oxiranylcarbostyril was disclosed in WO 95/25104 which involves multisteps for the synthesis and it employs the use of an expensive reagent like benzyltrimethylammonium dichloroiodate. The product is isolated using a tedious process.
WO 95/25104 also relates to a process for preparing (R)-8-benzyloxy-5-oxyranylcarbostyril, an intermediate of carmoterol, and there is no disclosure of a process for preparing carmoterol itself. A compound of formula (III) of WO95/25104 is reacted with the (R)-8-benzyloxy-5-oxiranylcarbostyril compound (II) to form a protected precursor to a carmoterol derivative. The compound (III) is in the form of a free amine. A disadvantage of the process for preparing the carmoterol derivative is that the use of free amine in excess gives rise to dimeric impurities as well as regioisomers which are difficult to separate.
The dimeric impurity of a precursor to carmoterol would have the following structure.

The regiosiomer of carmoterol would have the following structure.

A process for preparing an 8-(substituted oxy)-5-(R)-oxiranylcarbostyril oxiranyl compound is disclosed in patent application, WO 2004/076422. The process involves the use of a halo derivative for preparation of the corresponding halohydrin and cyclisation of the halohydrin to obtain the oxiranyl compound. However, there is no example disclosing the use of any halo compound other than the chloro compound.
WO 2004/076422 also relates to a process for preparing 5-[(R)-2-(5,6-diethyl-indan-2-yl-amino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one salt or solvate, and there is no disclosure of a process for preparing carmoterol itself. The compound 2-amino-(5,6-diethyl)-indan is reacted with the 8-(substituted oxy)-5-oxiranylcarbostyril compound to form a protected precursor to the indanyl compound. The 2-amino-(5,6-diethyl)-indan compound is in the form of a free amine. A disadvantage of the process for preparing 5-[(R)-2-(5,6-diethyl-indan-2-yl-amino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one salt or solvate is that the use of free amine in excess gives rise to dimeric impurities as well as regioisomers which are difficult to separate.
The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making optically pure carmoterol which is suitable for industrial scale up.
The present invention provides a process for synthesis of carmoterol which avoids all the disadvantages associated with prior art.